1 Preliminaries

1.1 Include

library(biovizBase)
library(ggbio)

library(FDb.InfiniumMethylation.hg19)

Known genes:

library(TxDb.Hsapiens.UCSC.hg19.knownGene)
txdb <- TxDb.Hsapiens.UCSC.hg19.knownGene 
library(EnsDb.Hsapiens.v75)
ensdb <- EnsDb.Hsapiens.v75 
library(SNPlocs.Hsapiens.dbSNP144.GRCh37)
snpdb <- SNPlocs.Hsapiens.dbSNP144.GRCh37

1.2 Settings

options(copdgene_ver_acs = 2)

1.3 Varibales

traits_cont <- copdgene_traits_main()[-1]
traits_bin <- copdgene_traits_main()[1]
traits_all <- c(traits_bin, traits_cont)

1.4 Association results

Single-trait asosciationr results:

tab1 <- copdgene_results_admixed(traits_cont, "SmokCigNow", 
  "~/git/hemostat/copdgene/results/07-scan-ver-4/rdata/")
tab2 <- copdgene_results_admixed(traits_cont, "SmokCigNow0_15", 
  "~/git/hemostat/copdgene/results/07-scan-ver-4/rdata/")

Multi-trait asosciationr results:

massoc1 <- readRDS(file.path(
  "~/git/hemostat/copdgene/results/07-scan-ver-4",
  "rdata/massoc.interaction.SmokCigNow.rds"))
massoc2 <- readRDS(file.path(
  "~/git/hemostat/copdgene/results/07-scan-ver-4",
  "rdata/massoc.interaction.SmokCigNow0_15.rds"))

2 Methylation summary stats

Article Genetically contextual effects of smoking on genome wide DNA methylation, 2017, Am J Med Genet B Neuropsychiatr Genet.

Data description

Results

Analysis Tests Significant Proprotion BF Threshold
Smoking effects 484,125 525 0.108% 1e-7
Interaction effects 126,369,511 827 0.0065% 3.96e-10
Interaction effects 195,068,554,297 448,242 0.00023% 2.60e-13

3 Chr 11, PARVA gene (interaction with SmokCigNow)

3.1 Manhattan plots

3.2 Fine-mapping

chr <- 11
start <- 12e6
end <- 13e6

gr1 <- GRanges("chr11", IRanges(start, end)) %>% range(ignore.strand = TRUE)

Table of top 10 SNPs:

rank snp zscore pval chr pos acs num_snps size trait
1 rs933920 2.928 0.003413 11 12,481,110 chr11acs76906 21 36,273 FEV1pp_utah
2 rs4553350 -2.847 0.004407 11 12,759,834 chr11acs76938 29 164,946 FEV1pp_utah
3 rs11022386 2.788 0.005301 11 12,548,017 chr11acs76922 2 2,166 FEV1pp_utah
4 rs6485989 2.719 0.006554 11 12,695,171 chr11acs76938 29 164,946 FEV1pp_utah
5 rs1564947 2.633 0.008467 11 12,176,409 chr11acs76843 24 23,173 FEV1pp_utah
6 rs4756884 -2.557 0.01055 11 12,474,098 chr11acs76906 21 36,273 FEV1pp_utah
7 rs901291 -2.528 0.01146 11 12,205,793 chr11acs76851 4 3,812 FEV1pp_utah
8 rs7131034 -2.499 0.01247 11 12,183,036 chr11acs76844 3 576 FEV1pp_utah
9 rs10831908 -2.452 0.0142 11 12,812,419 chr11acs76938 29 164,946 FEV1pp_utah
10 rs3812760 2.447 0.0144 11 12,557,016 chr11acs76925 21 25,500 FEV1pp_utah

Table of top 10 SNPs of top ancesty segment (chr11acs76906):

rank snp zscore pval chr pos acs num_snps size trait
1 rs933920 2.928 0.003413 11 12,481,110 chr11acs76906 21 36,273 FEV1pp_utah
6 rs4756884 -2.557 0.01055 11 12,474,098 chr11acs76906 21 36,273 FEV1pp_utah
11 rs4756866 -2.369 0.01781 11 12,448,846 chr11acs76906 21 36,273 FEV1pp_utah
23 rs10831815 2.076 0.03792 11 12,446,924 chr11acs76906 21 36,273 FEV1pp_utah
24 rs10741590 2.056 0.03976 11 12,463,318 chr11acs76906 21 36,273 FEV1pp_utah
31 rs1344615 -1.901 0.05725 11 12,454,046 chr11acs76906 21 36,273 FEV1pp_utah
53 rs11022358 1.647 0.09951 11 12,470,449 chr11acs76906 21 36,273 FEV1pp_utah
59 rs10831827 -1.603 0.1089 11 12,483,197 chr11acs76906 21 36,273 FEV1pp_utah
63 rs1365403 1.571 0.1161 11 12,476,231 chr11acs76906 21 36,273 FEV1pp_utah
67 rs1346220 1.543 0.1229 11 12,480,087 chr11acs76906 21 36,273 FEV1pp_utah

Gene model tracks:

List of genes: DKK3, MICAL2, MICALCL, PARVA, TEAD1.

Methylation tracks:

3.2.1 Meth. with cis SNP-by-smoking effects

CpG SNP Beta p-value Methylation Gene
cg20233228 rs16911103 -4.258 4.41e-13 TEAD1
cg20233228 rs16911106 -4.165 1.58e-12 TEAD1

Positions of meth. probes:

CpG probeStart probeEnd
cg20233228 12903562 12903611

Positions of SNPs in COPDGene dataset:

CpG SNP chr pos
cg20233228 rs16911103 NA NA
cg20233228 rs16911106 NA NA

Positions of SNPs in SNPdb:

CpG SNP chr pos
cg20233228 rs16911103 11 12,343,740
cg20233228 rs16911106 11 12,344,805

3.2.2 Meth. with trans SNP-by-smoking effects

10 (out of 167) rows with the largest effect sizes:

CpG SNP Beta p-value
cg25413748 rs658709 -516.9 NA
cg13569714 rs10840730 -278.1 NA
cg20233228 rs2175132 -12.58 NA
cg20233228 rs17036909 -12.56 NA
cg20233228 rs1396797 -12.49 NA
cg20233228 rs1396795 -12.49 NA
cg20233228 rs7953537 -12.21 NA
cg20233228 rs17094401 -12.21 NA
cg20233228 rs17094405 -12.2 NA
cg20233228 rs17094560 -12.16 NA

Positions of meth. probes:

CpG probeStart probeEnd
cg13569714 12,033,074 12,033,123
cg25413748 12,437,801 12,437,850
cg08647724 12,479,811 12,479,860
cg23384960 12,626,522 12,626,571
cg20233228 12,903,562 12,903,611

Positions of SNPs (top 10 effect sizes) in SNPdb:

CpG SNP chr pos
cg25413748 rs658709 20 3,587,400
cg13569714 rs10840730 12 17,662,085
cg20233228 rs2175132 2 69,887,369
cg20233228 rs17036909 2 69,883,592
cg20233228 rs1396797 2 69,872,657
cg20233228 rs1396795 2 69,872,562
cg20233228 rs7953537 12 44,693,288
cg20233228 rs17094401 12 44,696,784
cg20233228 rs17094405 12 44,700,415
cg20233228 rs17094560 12 44,769,768

4 Correlations among predictors for Ancestry and SNPs

   ---   orthogonalizing from global acs. 
Reading /Users/andreyziyatdinov/git/hemostat/copdgene/procdata/finemap/gdat2_chr11.rds 
Reading /Users/andreyziyatdinov/git/hemostat/copdgene/procdata/finemap/gdat2_chr11.bed 

5 Chr 2, TWIST2 gene (interaction with SmokCigNow0_15)

5.1 Manhattan plots

5.2 Fine-mapping

chr <- 2
start <- 237.75e6
end <- 239e6
end2 <- 240e6

gr2 <- GRanges("chr2", IRanges(start, end)) %>% range(ignore.strand = TRUE)

Table of top 10 SNPs:

rank snp zscore pval chr pos acs num_snps size trait
1 rs7597880 -2.801 0.005097 2 2.38e+08 chr2acs210672 2 84 FVC_utah
2 rs12613388 -2.759 0.005791 2 238,660,169 chr2acs210750 3 3,957 FVC_utah
3 rs3739051 -2.616 0.008892 2 2.39e+08 chr2acs210780 1 0 FVC_utah
4 rs2280289 2.369 0.01786 2 238,483,729 chr2acs210712 21 56,543 FVC_utah
5 rs7597414 -2.264 0.02359 2 2.38e+08 chr2acs210671 1 0 FVC_utah
6 rs2701336 2.261 0.02375 2 237,906,903 chr2acs210664 1 0 FVC_utah
7 rs2279642 -2.228 0.02591 2 238,682,770 chr2acs210753 21 97,602 FVC_utah
8 rs6431563 2.223 0.02621 2 238,804,355 chr2acs210764 1 0 FVC_utah
9 rs2701337 -2.218 0.02659 2 237,909,007 chr2acs210665 1 0 FVC_utah
10 rs10187629 -2.211 0.02701 2 238,640,263 chr2acs210747 2 1,258 FVC_utah

Table of top 10 SNPs of top ancesty segment (chr2acs210712):

rank snp zscore pval chr pos acs num_snps size trait
4 rs2280289 2.369 0.01786 2 238,483,729 chr2acs210712 21 56,543 FVC_utah
31 rs7598559 1.683 0.09237 2 238,435,398 chr2acs210712 21 56,543 FVC_utah
42 rs13394555 1.548 0.1217 2 238,483,322 chr2acs210712 21 56,543 FVC_utah
56 rs10190103 1.338 0.181 2 238,482,636 chr2acs210712 21 56,543 FVC_utah
114 rs2325814 -0.9431 0.3456 2 238,462,725 chr2acs210712 21 56,543 FVC_utah
124 rs6705903 -0.9155 0.3599 2 238,433,955 chr2acs210712 21 56,543 FVC_utah
125 rs2292881 0.9096 0.363 2 238,434,249 chr2acs210712 21 56,543 FVC_utah
151 rs2292877 -0.7854 0.4322 2 238,458,180 chr2acs210712 21 56,543 FVC_utah
154 rs1979763 -0.781 0.4348 2 238,436,481 chr2acs210712 21 56,543 FVC_utah
159 rs6766 0.7544 0.4506 2 238,483,164 chr2acs210712 21 56,543 FVC_utah

Gene model tracks:

List of genes: COL6A3, COPS8, LRRFIP1, MLPH, PRLH, RAB17, RAMP1, RBM44, SCLY, UBE2F, UBE2F-SCLY.

Methylation tracks:

5.3 Where is TWIST2?

List of (sorted) genes: ASB1, COL6A3, COPS8, ESPNL, HDAC4, HES6, ILKAP, KLHL30, LINC01107, LINC01940, LOC151174, LRRFIP1, MIR4440, MLPH, PER2, PRLH, RAB17, RAMP1, RBM44, SCLY, TRAF3IP1, TWIST2, UBE2F, UBE2F-SCLY.